Despite recent progress, mortality remains high in cows with severe abdominal crises, such as intestinal ischemia, salmonellosis, and neonatal septicemia (Morris 1991; Welch et al. 1992). Nationwide, pre-weaning heifer mortality rates approach 10%, with the majority of deaths attributed to diarrhea and systemic infection. In these acute inflammatory diseases, the inflammatory reaction is triggered with cytokines and the release of inflammatory mediators, with platelets activated either by endotoxins released from gram-negative bacteria and/or the coagulation cascade (Weiss and Rashid 1998). The inflammatory reaction can result in vascular injury and possibly thrombosis, which is the final and often fatal outcome of these disorders.
The inflammatory reaction begins with the tethering and rolling of the circulating leukocytes on an activated endothelium (McEver and Cummings 1997). The rolling process is mediated by the selectins, a family of Ca2+-dependent proteins. Membrane-bound selectins are expressed on the surface of endothelial cells (E-selectin), leukocytes (L-selectin), and platelets (P-selectin). All selectins contain a C-type carbohydrate recognition domain at their N-terminus which plays a crucial role in interacting with their ligand proteins.
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like glycoprotein constitutively expressed on leukocyte surfaces which binds to P-, E- and L-selectin. In humans, P-selectin/PSGL-1 binding plays a central role in inflammatory and thrombotic mechanisms in ischemic conditions by regulating leukocyte trafficking through cell adhesion, platelet-leukocyte aggregate formation and tissue factor expression. For instance, human P-selectin mediates leukocyte adhesion via its natural ligand, P-selectin glycoprotein ligand-1 (hPSGL-1). hPSGL-1 is located on the surface of a variety of leukocytes, including neutrophils, monocytes, eosinophils, and lymphocytes (Hicks et al. 2002). Human disorders associated with PSGL-1 binding share comparable pathomorphological features with common disorders in cattle, including enteritis, mastitis, and Haemophilus somnus infection, which can cause pneumonia, abortion, arthritis, septicemia, myocarditis and thromboembolic meningoencephalitis (TME). Due to the high basal state of platelet P-selectin expression, cows are likely predisposed to inflammatory and thrombotic disorders during gram-negative septicemia and endotoxemia as a result of enhanced platelet-leukocyte interaction via bovine PSGL-1 (bPSGL-1).
Treatments for these diseases in cattle include the use of antibiotics to treat the bacterial infection causing the inflammatory reaction and non-steroidal anti-inflammatory drugs (NSAIDs) to treat inflammatory symptoms. However, the use of antibiotics in food animals selects for resistant pathogens and resistance genes that may be transferred to humans through the consumption or handling of foods of animal origin. Recent studies have demonstrated that antimicrobial-resistance among food-borne bacteria may cause excess cases of illness, prolonged duration of illness, and increased rates of bacteremia, hospitalization, and death in humans. The continued availability of safe and effective antimicrobials for humans and animals depends upon the responsible use of these products.
Public health concerns related to the use of antibiotics and anti-inflammatory drugs in the dairy industry warrant the development of novel therapeutics that address the medical needs of the dairy industry yet respect these public health concerns. Additionally, the concurrent use of several of these pre-slaughter intervention strategies could synergistically decrease human illnesses by providing for additional barriers in a multiple-hurdle approach to improving food safety. A bovine-specific drug that reduces morbidity and mortality in dairy calves with scours or systemic infection will greatly impact the profit margin of dairy farmers while also reducing the prevalence of antibiotic resistant strains of bacteria entering the food chain and ‘illegal’ use of NSAIDs in food animals, a positive benefit to the food industry.
It can be appreciated that there exists a need in veterinary medicine for improved methods of treating bovine subjects susceptible to or suffering from acute inflammatory responses including scours and systemic infection. Methods to universally treat and/or prevent such disorders are highly sought after and their discovery would be welcomed by bovine owners and veterinarians alike.
Thus, an objective of the present application is to develop a bovine-specific molecule that targets cell adhesion molecules which regulate early events in leukocyte trafficking. Treatment with this molecule will likely minimize the vascular and organ tissue injury which is commonly associated with intestinal inflammation and septicemia.